Therapeutically active substituted nitrofurans of the imino series



Patented Feb. 18, 1947 um'rsn." s'rA'r1:-:s PATEVN 2.410.233 I THERAPEUTICAILY ac'rrvn snns'rrrn'rnn NITROFUBANS or'rnnmnnosnams William B. Stillman and Albert B. seem, 1

N.'Y., assignors, by mesno'aasignmenta-Ato v Eaton Laboratories, Inc., Norwich, 8.1.; a oor-v- I poration of New York No Drawing. Application May 17, Serial No. 53 6.0

10m (chm-u s) in association with variations of the side chain groupin produces compounds which are eflective against bacteria and many of which are active against infections in the animal body.

It has been found that outstanding antiseptic activity and also chemotherapeutic activity can be obtained from furan compounds which contain a nitro-group in the u-position, i. e. in the 2- or 5- position in the iuran ring, and which are substituted in at least one of the remaining (2 or 5) and 9 positions as follows:

E HNH Haze .84 ON wherein R represents hydrogen, alkyl or substituted alkyl, for example hydroxyalkyl, and Y represents alkyl, substituted alkyl such as hydroxyalkyl, alkoxy, amido, alkylamido, carbamido, carboxyalkyl or guanido.

The aforedescribed compounds may be prepared by condensing the aldehyde. -nitro furfural -cno o or the corresponding ketone -con (it having the above-indicated significance) with I anyone of a wide variety of compounds possess- .amino compounds. pounds may be employed as such or in the form of their acid salts or alkali metal compounds or ing a reactive amino group. The reactive amino compounds are so chosen that they will lead to the chemotherapeutically active configuration.

The scope of the invention thus includes all amino compounds which will lead to a side chain of this configuration.

Thus the condensation may be carried out between 5-nitro-2-furfural and, for example, one of the following reactive compounds: aminoguanidine, aminoguanidine sulfate, nitroaminoq guanidine, e-methyl- -aminoguanidine hydroiodide. a-ethyl-Y-aminoguanidine hydroiodide, a-n-butyl-y-aminoguanidine hydroiodide, etc.

Alternatively, 5-nitro-2-furyl methyl ketone may for example be condensed with these or similar The reactive amino comin any combination which will release the free amine under reaction conditions similar to those described in the following illustrative examples of condensations.

EXAIPLI I-- 5-nttro-z-jurjurylideneaminoyuanidinc sulfate Aminoguanidine sulfate (5 g.) was dissolved in water (100 00.). 5-nitro-2-furfural (5 g.) was added to the solution of aminoguanidine sulfate and the mixture was warmed for five minutes on the steam bath. The flask was then removed from the steam bath and swirled by hand until a precipitate formed. This required from ten-to flfteen minutes. The flask was then cooled in the refrigerator, after which the precipitate was removed by filtration. The product was recrystallized three times from water,-.using Darco (8.5 g. of crude material per 300 cc. of water). The purified material was a pale yellow color. It had no melting point, but charred and burned in a flame. It was the sulfate salt. The weight of purified material wa 5.5 g. yield). Solubility 1:750.

Exam 11 5-nitrojurfurylideneaminonitroguanidine 2m 2m 1 Nat-o +NH,.NH, Nmmrc NHNO: NHNO:

NB NmNEc I NHNO:

HNO,

\ Nitroaminoguanidine was prepared from nitroguanidine and hydrazine according to the procedure of Phillips and Williams, Jour. Am. Chem. Soc. 50, 2465 (1928). Then the nitroaminoguanidine was condensed with 5-nitrofurfural in aqueous solution essentially as described for the preparation of 5-nitrofurfurylideneaminoguanidine salts, to produce the fi-nitrofurfurylldeneaminonitroguanidine. i ExAmLn III S-nitrofurfurylidene-y-amino-a-methylguunidine 1 hlldroiodide /NH cmsc NHCH:

EXAMPLE. IV

5-nitrofurfurylidene-y-amino-a-ethyl guam'dine hydroiodide .HI H

1 NH case m NHLNH:

NHCIHI I NHaNEC I .m

ja-Ethyl-y-aminoguanidine hydroiodide was prepared from s-methyl N-ethyl isothiourea hydroiodide and hydrazine according to the procedure of Kirsten and Smith, Jour. Am. Chem. Soc. 58, 800 (1936). The a-ethyl-"y-aminoguanidine hydroiodide was then condensed with S-nitrofurfural in a, manner essentially as described for the preparation of 5-nitrofurfurylideneaminoguanidine sulfate, producing the 5-nitrofurfurylideney-amino-u-ethyl guanidine hydroiodide.

5-nitrofurfurylidene-- -amino--n-but1/l ExAmLa V guanidine hydroiodide a-n-Butyl-v-aminoguanidine hydroiodide' was prepared from S-methyl N-ethyl isothiourea hydroiodide and hydrazine according to the procedure of Kirsten and Smith, Jour. Am. Chem. Soc. 58, 800 (1936) The a-n-butyl-y-aminoguanidine hydroiodide was then condensed with 5-nitr0furfural essentially as described for the preparation of 5-nitrofurfurylidene aminoguanidine sulfate,

to produce the 5-nitrofurfurylidene-'y-amino-- n-butyl guanidine hydroiodide.

The compounds according to the present invention can be used locally against bacterial infections. For this purpose they can be employed as solutions, emulsions or ointments. Also, some of these compounds have been found to be eflective in animals, when administered orally, against fatal infections obtained by inoculation with streptococci and trypanosomes.

Having thus disclosed the invention. what is claimed is:

1. A new chemical compound having chemo therapeutic activity and represented by the forin which R represents a member. of the group consisting of hydrogen, alkyl and hydroxyalkyl, and Y represents a member of the group consisting of amido, alkylamido, nitroamido, carbamido and guanido, and the salts thereof.

2. 5-nitrofurfurylidene aminoguanidine represented by the formula:

3. A salt of the compound claimed in the next preceding claim.

4. 5-nitro-2-furfurylideneaminoguanidine sulfate represented by the formula:

5. 5 nitrofurturylideneaminonltrcguanidine represented by the formula: CB8 N The following references are of record in the I H I file of this patent: o N I 5 UNITED s'rxms mum's v Number Name Date 6. 5- nitrofurfurylidene '1 amino meth- 2361-735 Gemer at at Nov. 4' 1941 ylguanidine represented by the formula; 2,310,004 Widmer et al. Feb. 2, 194a NH 10 1,780,636 Stine Nov. 4, 1930 0r-[1CH=NNH.O OTHER, REFER-WCES Heiibron, Dictionary of Organic Compounds,

NECK:

- 1 3 51. in 7. A salt of the compound claimed in the next 15 i gg i a d? 193 322 2: preceding claim. (copy in Div. 6.)

I WIILIAM B. B'I'IILMAN.

AIBERT B. scorn. 

